Stem Cell-Directed Nanotheranostics for Cancer Intervention Progress in cancer biology and drug delivery approaches have not adequately translated into clinical advances in the diagnosis or treatment of cancer. This disconnect is rooted in the inefficient delivery of imaging and therapeutic agents to the tumor site upon systemic delivery. It is now well-known that a multitude of biological barriers exist that pose insurmountable obstacles impeding the proper bio-distribution, and limiting the ability of the agent to effectively localize at the target. Recently, novel classes of agents capable of providing non- invasive imaging and targeted drug delivery, known as theranostic agents, have emerged. Nanoparticles (NPs) have surfaced as potential theranostic vectors capable of delivering both types of agents specifically to pathological sites. However to evolve as effective theranostic agents for systemic administration, NPs must sequentially evade these biobarriers. Moreover, even after decoration with targeting moieties, NPs have failed to accumulate at the tumor site at dosages that guarantee therapy, resulting in toxicity to healthy organs and a wide array of side effects at the expense of treatment. Herein I propose to decouple the homing and therapeutic responsibilities of NPs by creating a platform capable of providing solutions to the aforementioned problems. In this approach, the natural tumor tropism of adipose stem cells (ASC) will be combined with multistage silicon nanoshuttles (MSN) ability to carry a diverse array of NPs and release them in a controlled fashion. I believe that the optimal loading of superparamagnetic iron oxide and doxorubicin-encapsulated NP into MSNs will provide for the ideal theranostic approach needed to image and treat cancer. The ASCs will in turn internalize the loaded-MSNs and mediate their selective delivery to the tumor site. Once the target has been reached, the ASC will release MSNs within the tumor microenvironment. Thereafter, the MSNs will then deploy the payload, which can be used for cancer imaging and therapy. [This proposal is designed to challenge me by requiring me to become proficient in multiple areas, a prerequisite necessary for a successful career in biomedical research and nanomedicine. Working in the labs of Dr. Ferrari and Li, will allow for the opportunity to acquire and refine several techniques such as nanoparticle characterization, in vitro drug toxicity assays and imaging. In addition, the plan allows for me to attain training to enhance my presentation, grant writing and critical analysis skills through a combination of seminars, retreats, courses and exposure to other investigators labs.] I believe the beneficial combination of stem cell biology with nanotechnology will provide for an extremely novel and elegant solution to the current unsolved limitations in drug delivery and molecular imaging. The anticipated benefits from this platform include: 1) Avoidance of barriers by ASC mediated delivery;2) Protection against inadvertent release of theranostic NPs;3) Localized delivery of NPs by homing of ASC to tumor;and 4) Controlled release and accumulation of theranostic NPs upon release from MSNs. PUBLIC HEALTH RELEVANCE: New effective approaches for the diagnosis and treatment of cancer are urgently needed. The aim of the proposed research is to create an innovative delivery system for the efficacious treatment and the accurate imaging of cancer. This work will establish a viable platform for the diagnosis and therapy of cancer with immense potential for benefiting both the public (increasing cancer patient survival) and the economy (reducing total treatment cost).